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Modulation, Bioinformatic Screening, and Assessment of Small Molecular Peptides Targeting the Vascular Endothelial Growth Factor Receptor
Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) are important factors in tumor growth and metastasis. Molecular probes or drugs designed to target VEGF/VEGFR interactions are crucial in tumor molecular imaging and targeted therapy. Bioinformatic methods enable molecular design ba...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224745/ https://www.ncbi.nlm.nih.gov/pubmed/25069724 http://dx.doi.org/10.1007/s12013-014-0151-x |
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author | Feng, Shibin Zou, Lingyun Ni, Qingshan Zhang, Xiang Li, Qianwei Zheng, Lei Xie, Laiping Li, Hongmin Huang, Dingde |
author_facet | Feng, Shibin Zou, Lingyun Ni, Qingshan Zhang, Xiang Li, Qianwei Zheng, Lei Xie, Laiping Li, Hongmin Huang, Dingde |
author_sort | Feng, Shibin |
collection | PubMed |
description | Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) are important factors in tumor growth and metastasis. Molecular probes or drugs designed to target VEGF/VEGFR interactions are crucial in tumor molecular imaging and targeted therapy. Bioinformatic methods enable molecular design based on the structure of bio-macromolecules and their interactions. This study was aimed to identify tumor-targeting small-molecule peptides with high affinity for VEGFR using bioinformatics screening. The VEGFR extracellular immunoglobulin-like modules Ig1–Ig3 were used as the target to systematically alter the primary peptide sequence of VEGF(125–136). Molecular docking and surface functional group interaction methods were combined in an in silico screen for polypeptides, which in theory, would have higher affinities for VEGFR. In vitro receptor competition binding assays were used to assess the affinity of the putative VEGFR-binding polypeptides. Rhodamine-conjugated peptides were used to label and visualize peptide-binding sites on A549 cells. Using bioinformatic screening, we identified 20 polypeptides with potentially higher affinity for VEGFR. The polypeptides were capable of inhibiting the binding of (125)I-VEGF to VEGFR in a dose-dependent manner. The IC(50) values of QKRKRKKSRKKH and RKRKRKKSRYIVLS (80 and 185 nmol/L, respectively) were significantly lower than that of VEGF(125–136) (464 nmol/L); thus, the affinity of these peptides for VEGFR was 6- and 2.5-fold higher, respectively, than that of VEGF(125–136). Rhodamine labeling of A549 cells revealed peptide binding mainly on the plasma membrane and in the cytoplasm. Bioinformatic approaches hold promise for the development of molecular imaging probes. Using this approach, we designed two peptides that showed higher affinity toward VEGFR. These polypeptides may be used as molecular probes or drugs targeting VEGFR, which can be utilized in molecular imaging and targeted therapy of certain tumors. |
format | Online Article Text |
id | pubmed-4224745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-42247452014-11-12 Modulation, Bioinformatic Screening, and Assessment of Small Molecular Peptides Targeting the Vascular Endothelial Growth Factor Receptor Feng, Shibin Zou, Lingyun Ni, Qingshan Zhang, Xiang Li, Qianwei Zheng, Lei Xie, Laiping Li, Hongmin Huang, Dingde Cell Biochem Biophys Original Paper Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) are important factors in tumor growth and metastasis. Molecular probes or drugs designed to target VEGF/VEGFR interactions are crucial in tumor molecular imaging and targeted therapy. Bioinformatic methods enable molecular design based on the structure of bio-macromolecules and their interactions. This study was aimed to identify tumor-targeting small-molecule peptides with high affinity for VEGFR using bioinformatics screening. The VEGFR extracellular immunoglobulin-like modules Ig1–Ig3 were used as the target to systematically alter the primary peptide sequence of VEGF(125–136). Molecular docking and surface functional group interaction methods were combined in an in silico screen for polypeptides, which in theory, would have higher affinities for VEGFR. In vitro receptor competition binding assays were used to assess the affinity of the putative VEGFR-binding polypeptides. Rhodamine-conjugated peptides were used to label and visualize peptide-binding sites on A549 cells. Using bioinformatic screening, we identified 20 polypeptides with potentially higher affinity for VEGFR. The polypeptides were capable of inhibiting the binding of (125)I-VEGF to VEGFR in a dose-dependent manner. The IC(50) values of QKRKRKKSRKKH and RKRKRKKSRYIVLS (80 and 185 nmol/L, respectively) were significantly lower than that of VEGF(125–136) (464 nmol/L); thus, the affinity of these peptides for VEGFR was 6- and 2.5-fold higher, respectively, than that of VEGF(125–136). Rhodamine labeling of A549 cells revealed peptide binding mainly on the plasma membrane and in the cytoplasm. Bioinformatic approaches hold promise for the development of molecular imaging probes. Using this approach, we designed two peptides that showed higher affinity toward VEGFR. These polypeptides may be used as molecular probes or drugs targeting VEGFR, which can be utilized in molecular imaging and targeted therapy of certain tumors. Springer US 2014-07-29 2014 /pmc/articles/PMC4224745/ /pubmed/25069724 http://dx.doi.org/10.1007/s12013-014-0151-x Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Paper Feng, Shibin Zou, Lingyun Ni, Qingshan Zhang, Xiang Li, Qianwei Zheng, Lei Xie, Laiping Li, Hongmin Huang, Dingde Modulation, Bioinformatic Screening, and Assessment of Small Molecular Peptides Targeting the Vascular Endothelial Growth Factor Receptor |
title | Modulation, Bioinformatic Screening, and Assessment of Small Molecular Peptides Targeting the Vascular Endothelial Growth Factor Receptor |
title_full | Modulation, Bioinformatic Screening, and Assessment of Small Molecular Peptides Targeting the Vascular Endothelial Growth Factor Receptor |
title_fullStr | Modulation, Bioinformatic Screening, and Assessment of Small Molecular Peptides Targeting the Vascular Endothelial Growth Factor Receptor |
title_full_unstemmed | Modulation, Bioinformatic Screening, and Assessment of Small Molecular Peptides Targeting the Vascular Endothelial Growth Factor Receptor |
title_short | Modulation, Bioinformatic Screening, and Assessment of Small Molecular Peptides Targeting the Vascular Endothelial Growth Factor Receptor |
title_sort | modulation, bioinformatic screening, and assessment of small molecular peptides targeting the vascular endothelial growth factor receptor |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224745/ https://www.ncbi.nlm.nih.gov/pubmed/25069724 http://dx.doi.org/10.1007/s12013-014-0151-x |
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